MHC class I genes are affected by a variety of exogenous stimuli which can either increase or decrease levels of expression. Although agents such as TNF and interferon are well known modulators of class I genes, many other factors also alter expression. We recently observed that the hormone TSH specifically reduces transcription of endogenous class I genes in cultured thyrocytes. Thyrocytes normally express MHC class I, as does a rat thyrocyte cell line, FRTL5. TSH treatment of FRTL-5 cells decreases transcription of both TSH receptor and class I genes. This down-regulation is cAMP mediated and TSH receptor dependent. The ability of cAMP to reduce class I gene expression is not limited to the thyrocyte line. A variety of cells, including lymphoblastoid and fibroblasts, also decrease class I expression in response to cAMP. Although no canonical CRE is found within the 5' upstream region of the class I genes, a series of 5' deletion mutants ligated to the reporter gene, CAT, is being used to functionally localize the cAMP responsive element. Other agents (including insulin, hydrocortisone, and serum) are capable of modulating class I expression. Serum acts as a negative regulator of class 1, both at the cell surface and in steady-state levels of RNA, in a variety of cells. The DNA element responsive to serum maps to a constitutive negative regulatory element, RE-105. Analysis of RE-105 does not reveal a recognizable serum response element (SRE). Since the composition of serum is complex and its effects are pleiotropic, the active component in the serum is not known. However, c-jun, which is stimulated following serum treatment, is found to be a negative regulator of class I expression.